The ultimate goal of this project is to find an agent that will cause a reversal of preneoplasia in epithelial tissue. Vitamin A and its analogs (retinoids) are the compounds currently being investigated. Emphasis has been placed on examining the metabolic pathway of a natural retinoid, all-transretinoic acid in vivo and in vitro. Retinoic acid has been shown to undergo a tissue dependent metabolism to several more polar compounds in a hamster tracheal organ culture system. Two of these metabolites have been identified as 4-hydroxy-retinoic acid and 4-keto-retinoic acid. A comparison of the in vivo and in vitro metabolism of all-transretinoic acid versus 13-cis-retinoic acid suggests that both compounds may be sharing a common metabolic pathway that may include an isomeric form of 4-keto-retinoic acid. A knowledge of the metabolic pathway of retinoic acid will help to decipher the biochemical mechanism of action of vitamin A in determining epithelial cell differentiation. It will also aid in designing analogs of vitamin A that will display biological activity in the reversal of preneoplasia and, at the same time, will indicate low toxicity in the animal.